Chronic wounds have emerged as a tough clinical challenge. An improved understanding of wound-healing mechanisms is paramount. Collagen XVII (COL17), a pivotal constituent of hemidesmosomes, holds considerable promise for regulating epidermal cell adhesion to the basement membrane as well as for epidermal cell motility and self-renewal of epidermal stem cells. However, the precise role of COL17 in wound repair remains elusive, and the upstream regulatory mechanisms involved have not been fully elucidated. In this study, we delineated the temporal and spatial expression patterns of COL17 at the epidermal wound edge. Subsequently, we investigated the indispensable role of COL17 in keratinocyte activation and reepithelialization during wound healing, demonstrating the restoration of the normal repair process by COL17 overexpression in diabetic wounds. Notably, we identified a key transcriptional signaling pathway for COL17, wherein pyruvate kinase isozyme M2 (PKM2) promotes phosphorylation of STAT3, leading to its activation and subsequent induction of COL17 expression upon injury. Ultimately, by manipulating this pathway using the PKM2 nuclear translocator SAICAR, we revealed a promising therapeutic strategy for enhancing the healing of chronic wounds.